Use of "N-in-One" dosing to create an in vivo pharmacokinetics database for use in developing structure-pharmacokinetic relationships

The purpose of this work was (1) to determine if useful in vivo pharmacokin etic data could be obtained after simultaneous administration of 5-22 compo unds of a chemically congeneric series to dogs and (2) to determine if stru cture-pharmacokinetic relationships could be derived from such studies. Mix tures of structurally related CL-I antagonist compounds (5-22) were adminis tered intravenously to conscious dogs. Blood samples were taken over the ne xt 24 h and analyzed by LC/MS to determine plasma levels and pharmacokineti cs of each compound. The pharmacokinetics of 17 of these compounds were als o determined after individual administration. Results obtained in the N-in- One format for 17 compounds correlated well with results obtained when thes e same compounds were administered individually. The N-in-One method is a u seful method for obtaining pharmacokinetic data on 5-20 molecules in a sing le animal at one time. The increased throughput in obtaining important phar macokinetic information should enhance the drug discovery process. In addit ion, it was possible to determine the extent to which various chemical subs titutions did or did not affect pharmacokinetic parameters.